Store-independent Orai1/3 channels activated by intracrine leukotriene C4: role in neointimal hyperplasia

Circ Res. 2013 Mar 29;112(7):1013-25. doi: 10.1161/CIRCRESAHA.111.300220. Epub 2013 Jan 24.


Rationale: Through largely unknown mechanisms, Ca(2+) signaling plays important roles in vascular smooth muscle cell (VSMC) remodeling. Orai1-encoded store-operated Ca(2+) entry has recently emerged as an important player in VSMC remodeling. However, the role of the exclusively mammalian Orai3 protein in native VSMC Ca(2+) entry pathways, its upregulation during VSMC remodeling, and its contribution to neointima formation remain unknown.

Objective: The goal of this study was to determine the agonist-evoked Ca(2+) entry pathway contributed by Orai3; Orai3 potential upregulation and role during neointima formation after balloon injury of rat carotid arteries.

Methods and results: Ca(2+) imaging and patch-clamp recordings showed that although the platelet-derived growth factor activates the canonical Ca(2+) release-activated Ca(2+) channels via store depletion in VSMC, the pathophysiological agonist thrombin activates a distinct Ca(2+)-selective channel contributed by Orai1, Orai3, and stromal interacting molecule1 in the same cells. Unexpectedly, Ca(2+) store depletion is not required for activation of Orai1/3 channel by thrombin. Rather, the signal for Orai1/3 channel activation is cytosolic leukotrieneC4 produced downstream thrombin receptor stimulation through the catalytic activity of leukotrieneC4 synthase. Importantly, Orai3 is upregulated in an animal model of VSMC neointimal remodeling, and in vivo Orai3 knockdown inhibits neointima formation.

Conclusions: These results demonstrate that distinct native Ca(2+)-selective Orai channels are activated by different agonists/pathways and uncover a mechanism whereby leukotrieneC4 acts through hitherto unknown intracrine mode to elicit store-independent Ca(2+) signaling that promotes vascular occlusive disease. Orai3 and Orai3-containing channels provide novel targets for control of VSMC remodeling during vascular injury or disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angioplasty, Balloon / adverse effects
  • Animals
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Calcium Channels / physiology*
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology
  • Carotid Artery Injuries / etiology
  • Carotid Artery Injuries / pathology
  • Carotid Artery Injuries / physiopathology*
  • Cytosol / metabolism
  • Disease Models, Animal
  • Leukotriene C4 / metabolism*
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Muscle, Smooth, Vascular / physiopathology*
  • Neointima / etiology
  • Neointima / pathology
  • Neointima / physiopathology*
  • ORAI1 Protein
  • Patch-Clamp Techniques
  • Platelet-Derived Growth Factor / metabolism
  • Platelet-Derived Growth Factor / pharmacology
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Stromal Interaction Molecule 1
  • Thrombin / metabolism
  • Thrombin / pharmacology


  • Calcium Channels
  • Membrane Glycoproteins
  • ORAI1 Protein
  • Orai1 protein, rat
  • Orai3 protein, rat
  • Platelet-Derived Growth Factor
  • RNA, Small Interfering
  • Stim1 protein, rat
  • Stromal Interaction Molecule 1
  • Leukotriene C4
  • Thrombin